PURPOSE: Despite morbidities and fatalities, nationwide epidemiologic data for severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS), are not widely available. We aimed to investigate SCAR epidemiology over the last two decades in Korea. MATERIALS AND METHODS: We analyzed individual case safety reports (ICSRs) of SCARs in the Korea Adverse Event Reporting System from 1988 to 2013. Administered drugs, demographic profiles, and causality assessment according to the World Health Organization-Uppsala Monitoring Center system were analyzed. RESULTS: A total of 755 SCAR cases (508 SJS/TEN, 247 DRESS) were reported. The number of SCAR ICSRs has been increasing with increasing ICSRs for overall adverse drug events. Since 2010, the number of SCAR ICSRs has increased up to 100 cases/year. Allopurinol was the most common causative drug (SJS/TEN: 10.2%; DRESS: 11.3%; SCAR ICSRs: 10.6%), followed by carbamazepine (SJS/TEN: 8.7%; DRESS: 9.7%; SCAR ICSRs: 8.6%). Regarding drug groups, antiepileptics (19.5%) and antibiotics for systemic use (12.7%) were common causative drug groups. Twenty SCAR-related deaths were recorded. Antibacterials were the most common causes of deaths (8 cases), followed by antiepileptics (5 cases). The potential risk of SCARs was not specified in the drug information leaflet for 40.2% of drugs causing SJS/TEN and 82.5% causing DRESS syndrome in Korea. CONCLUSION: The number of SCAR ICSRs has increased rapidly with recent active pharmacovigilance programs in Korea. Allopurinol and antiepileptics are the most common individual and categorical causative agents, respectively.
Allopurinol ; Anti-Bacterial Agents ; Anticonvulsants ; Carbamazepine ; Cause of Death ; Cicatrix ; Drug Hypersensitivity Syndrome ; Drug-Related Side Effects and Adverse Reactions ; Epidemiology ; Global Health ; Korea ; Pharmacovigilance ; Stevens-Johnson Syndrome

Adverse drug reactions can cause considerable discomfort. They can be life-threatening in severe cases, requiring or prolonging hospitalization, impeding proper treatment, and increasing treatment costs considerably. Although the incidence of severe cutaneous adverse reactions (SCARs) is low, they can be serious, have permanent sequelae, or lead to death. A recent pharmacogenomic study confirmed that genetic factors can predispose an individual to SCARs. Genetic markers enable not only elucidation of the pathogenesis of SCARs, but also screening of susceptible subjects. The human leukocyte antigen (HLA) genotypes associated with SCARs include HLA-B*57:01 for abacavir (Caucasians), HLA-B*58:01 for allopurinol (Asians), HLA-B*15:02 (Han Chinese) and HLA-A*31:01 (Europeans and Koreans) for carbamazepine, HLA-B*59:01 for methazolamide (Koreans and Japanese), and HLA-B*13:01 for dapsone (Asians). Therefore, prescreening genetic testing could prevent severe drug hypersensitivity reactions. Large-scale epidemiologic studies are required to demonstrate the usefulness and cost-effectiveness of screening tests because their efficacy is affected by the genetic differences among ethnicities.
Allopurinol ; Carbamazepine ; Cicatrix ; Dapsone ; Drug Hypersensitivity ; Drug Hypersensitivity Syndrome ; Drug-Related Side Effects and Adverse Reactions ; Epidemiologic Studies ; Genetic Markers* ; Genetic Testing ; Genotype ; Health Care Costs ; HLA Antigens ; Hospitalization ; Humans ; Incidence ; Leukocytes ; Mass Screening ; Methazolamide ; Pharmacogenetics ; Stevens-Johnson Syndrome

BACKGROUND/AIMS: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe cutaneous adverse reactions that frequently result in fatal outcomes. We investigated cases of SJS and TEN in a regional hospital. METHODS: From 2008 to 2014, SJS and TEN cases were enrolled retrospectively by allergy and dermatology specialists, and their clinical features and severity-of-illness score for TEN (SCORTEN) were assessed. RESULTS: During the 7-year study period, 56 SJS and 14 TEN cases were recruited. The majority (71%) were 40-70 years of age (mean age of male and female patients, 55 and 54 years, respectively). Regarding drugs, anticonvulsants (42.8%) were the most frequently causative, followed by carbonic anhydrase inhibitors (20.0%), antimicrobials (15.7%), allopurinol (7.1%), and non-steroidal anti-inflammatory drugs (7.1%). No fatal case of SJS was seen. However, 7 of the 14 patients with TEN died (50%; mean age, 67 years; 1 of 5 [20%] males and 6 of 9 females [66.7%]). The mortality rate was reflected in the SCORTEN values. Vancomycin, allopurinol, methazolamide (two cases each) and megestrol (one case) were the causative drugs in the seven fatal TEN cases. Treatment modality did not affect the likelihood of death due to TEN. CONCLUSIONS: The causative drugs of, and frequency of mortality due to, SJS and TEN should be recognized by physicians. Elderly females with TEN are at high risk of mortality. SCORTEN values reflect the mortality rate of TEN patients. Early recognition and proper management of SJS and TEN may reduce the mortality rate.
Aged ; Allopurinol ; Anticonvulsants ; Carbonic Anhydrase Inhibitors ; Dermatology ; Drug-Related Side Effects and Adverse Reactions ; Fatal Outcome ; Female ; Humans ; Hypersensitivity ; Male ; Megestrol ; Methazolamide ; Mortality ; Retrospective Studies ; Specialization ; Stevens-Johnson Syndrome* ; Vancomycin

BACKGROUND: Drug reaction with eosinophilia and systemic symptoms (DRESS) is a syndrome involving multiple organs. Due to a variable clinical presentation and uncertain definition, diagnosis is often delayed or misdiagnosed. OBJECTIVE: The purpose of this study was to investigate the common causative drugs of DRESS and differences according to drugs, clinical features, and prognosis of DRESS, and secondly to compare the differences between steroid use group versus non-use group. METHODS: Medical records of hospitalized patients at the Sanggye Paik Hospital from January 2001 to December 2015 were collected. DRESS patients were enrolled retrospectively using the RegiSCAR diagnostic criteria. RESULTS: A total of 65 patients were included. The four most common causative drug groups were antibiotics (27.7%), anticonvulsants (20%), antituberculosis agents (16.9%), and allopurinol (16.9%). The mean incubation period was 4 weeks, significantly shorter in antibiotics (2 weeks, p < 0.001) and significantly longer in anticonvulsants (6.5 weeks, p=0.033). Sixty-three patients fully recovered with a mean recovery time of 3.1 (standard deviation 2.2) weeks, one patient had sequelae, and one patient died. Recovery time tended to increase with longer duration of diagnosis from rash onset (p < 0.001, correlation coefficient=0.419) and higher serum aspartate aminotransferase levels (p=0.024, correlation coefficient=0.297). The mean recovery time was 1 week shorter for the systemic steroid use group, but it was not statistically significant (p=0.056). CONCLUSION: DRESS may be a heterogeneous syndrome with specific characteristics related to different drugs. The prognosis of DRESS is relatively good and the role of systemic steroid therapy is unclear. Prompt diagnosis and immediate discontinuation of the causative drug are essential for early recovery.
Allopurinol ; Anti-Bacterial Agents ; Anticonvulsants ; Aspartate Aminotransferases ; Diagnosis ; Drug Hypersensitivity ; Drug Hypersensitivity Syndrome* ; Drug-Related Side Effects and Adverse Reactions ; Exanthema ; Humans ; Medical Records ; Prognosis ; Retrospective Studies*

PURPOSE: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are very serious forms of drug-induced cutaneous adverse reaction. SJS/TEN induced by certain drug is well known to be associated with some human leukocyte antigen (HLA) gene type. We aimed to explore HLA allele frequencies and their association with SJS/TEN according to culprit drugs in Korea. MATERIALS AND METHODS: We enrolled 5802 subjects who had results of HLA typing test from August 2005 to July 2014. Total 28 SJS/TEN patients were categorized based on culprit drugs (allopurinol, lamotrigine, carbamazepine) and identified the presence of HLA-B*58:01, HLA-B*44:03, HLA-B*15:02, and HLA-A*31:01. RESULTS: HLA-A*24:02 (20.5%), HLA-B*44:03 (10.0%), and HLA-Cw*01:02 (17.1%) were the most frequent type in HLA-A, -B, and -C genes, respectively. Allele frequencies of HLA-B*58:01, HLA-B*44:03, HLA-A*31:01, and HLA-B*15:02 were 7.0%, 10.0%, 5.0%, and 0.3%, respectively. In 958 allopurinol users, 9 subjects (0.9%) were diagnosed with SJS/TEN. Among them, 8 subjects possessed HLA-B*58:01 allele. SJS/TEN induced by allopurinol was more frequently developed in subjects with HLA-B*58:01 than in subjects without it [odds ratio: 57.4; confidence interval (CI) 7.12-463.50; p<0.001]. Allopurinol treatment, based on screening by HLA-B*58:01 genotyping, could be more cost-effective than that not based on screening. HLA-B*44:03 may be associated with lamotrigine-induced SJS/TEN (odds ratio: 12.75; CI 1.03-157.14; p=0.053). Among carbamazepine users, only two patients experienced SJS/TEN and possessed neither HLA-B*15:02 nor HLA-A*31:03. CONCLUSION: HLA gene frequencies varied in Korea. Screening of HLA-B*58:01 before the use of allopurinol might be needed to anticipate probability of SJS/TEN.
Adult ; Aged ; *Alleles ; Allopurinol/adverse effects/*pharmacology ; Anticonvulsants/*adverse effects ; Asian Continental Ancestry Group/*genetics ; Carbamazepine/adverse effects/*pharmacology ; Case-Control Studies ; Drug-Related Side Effects and Adverse Reactions/*genetics/immunology ; Female ; Gene Frequency ; Genetic Predisposition to Disease ; Genotype ; HLA-B Antigens/*genetics ; Humans ; Male ; Middle Aged ; Odds Ratio ; Polymorphism, Single Nucleotide ; Republic of Korea ; Retrospective Studies ; Risk Factors ; Stevens-Johnson Syndrome/ethnology/etiology/*genetics ; Triazines/adverse effects/*pharmacology

BACKGROUND/AIMS: Allopurinol is a urate-lowering agent that is commonly used to prevent chemotherapy-related hyperuricemia. Allopurinol hypersensitivity syndrome (AHS) is a disorder involving multiple organs, which may be accompanied by cutaneous adverse reactions. We identified the characteristics and clinical outcomes of chemotherapy-associated AHS in patients with hematological malignancies. METHODS: This retrospective single-center study included 26 AHS patients (11 with and 15 without hematological malignancies) admitted to Seoul St. Mary's Hospital. AHS was defined using the criteria of Singer and Wallace. Comparisons were made using the Mann-Whitney U test and Fisher exact test as appropriate. RESULTS: In patients with a hematological malignancy and AHS, statistically significant differences were observed in terms of younger age at onset; shorter duration of exposure; higher starting and maintenance doses of allopurinol; lower incidence of eosinophilia, leukocytosis, and underlying renal insufficiency; and more frequent occurrence of fever compared to AHS patients without a hematological malignancy. Two AHS patients with a hematological malignancy were examined for human leukocyte antigen (HLA)-B typing, but neither patient harbored the HLA-B*5801 allele. All of the patients ceased allopurinol treatment, with most patients making a full recovery. Two patients in the study died; however, these deaths were unrelated to AHS. One patient developed serious sequelae of AHS that required hemodialysis. CONCLUSIONS: Physicians who prescribe allopurinol for the prevention of chemotherapy-related hyperuricemia should be aware of the unique risk of AHS, even in patients with hematological malignancies who do not have known risk factors for AHS. Novel urate-lowering agents should be considered alternative treatments.
Adolescent ; Adult ; Age Factors ; Aged ; Allopurinol/*adverse effects ; Antineoplastic Agents/*adverse effects ; Comorbidity ; Dose-Response Relationship, Drug ; Drug Hypersensitivity Syndrome/diagnosis/drug therapy/*etiology ; Female ; Glucocorticoids/therapeutic use ; Gout Suppressants/*adverse effects ; Hematologic Neoplasms/*drug therapy ; Humans ; Hyperuricemia/chemically induced/diagnosis/*prevention & control ; Male ; Medical Records ; Middle Aged ; Republic of Korea ; Retrospective Studies ; Risk Factors ; Treatment Outcome ; Young Adult

Toxic epidermal necrolysis is an unpredictable and severe adverse drug reaction. In toxic epidermal necrolysis, epidermal damage appears to result from keratinocyte apoptosis. This condition is triggered by many factors, principally drugs such as antiepileptic medications, antibiotics (particularly sulfonamide), nonsteroidal anti-inflammatory drugs, allopurinol, and nevirapine. Lamotrigine has been reported potentially cause serious cutaneous reactions, and concomitant use of valproic acid with lamotrigine significantly increases this risk. We describe a case of an 11-year-old girl with tic and major depressive disorders who developed toxic epidermal necrolysis after treatment with lamotrigine, and who was diagnosed both clinically and pathologically. Children are more susceptible to lamotrigine-induced rash than adults, and risk of serious rash can be lessened by strict adherence to dosing guidelines. Unfortunately, in our case, the patient was administered a higher dose than the required regimen. Therefore, clinicians should strictly adhere to the dose regimen when using lamotrigine, especially in children.
Adult ; Allopurinol ; Anti-Bacterial Agents ; Apoptosis ; Child* ; Depressive Disorder, Major ; Drug-Related Side Effects and Adverse Reactions ; Exanthema ; Female ; Humans ; Keratinocytes ; Nevirapine ; Stevens-Johnson Syndrome* ; Tics ; Valproic Acid

Drug allergy exhibits a wide range of clinical features that partly reflect the diversity of the underlying responsible mechanisms. These range from non-immunologic idiosyncratic reactions to Gell and Coombs type 1, 2, 3, and 4 reactions. Consequently, a drug allergy may be difficult to differentiate from an adverse drug reaction. The prevalence of drug allergy varies but is assumed to account for 30% of all adverse drug reactions. In the U.S., 3.1-6.2% of all ward patients are admitted because of adverse drug reactions, and 5-10% of all out-patients or ward patients have suffered an adverse drug reaction. Nonsteroidal anti-inflammatory drugs (NSAIDs), antibiotics, and radiocontrast media are the most common causes of drug allergy, but with the recent introduction of molecular anti-cancer agents, the number of drug allergy cases by these agents is soaring. Drug allergy is an important cause of mortality in admitted patients, and 1 out of every 10,000 admitted patients will die because of a drug allergy. Approximately 30% of adverse drug reactions can be prevented if previous reactions have been monitored and managed adequately. In 2006, a regional pharmacovigilance program was launched in Korea. In addition, the Korean Institute of Drug Safety and Risk Management plans to develop a nationwide drug utilization review program to monitor adverse drug reactions and to provide relevant information from the program to health professionals working in hospitals and clinics, with the aim of preventing drug allergies. Recent studies have shown a strong association between human leukocyte antigen genotypes and the severe cutaneous adverse reactions (SCARs) induced by certain drugs. Genotype prescreening may contribute to the prevention of SCARs induced by culprit drugs such as carbamazepine, allopurinol, and abacavir.
Allopurinol ; Anti-Bacterial Agents ; Carbamazepine ; Cicatrix ; Contrast Media ; Drug Hypersensitivity* ; Drug Utilization Review ; Drug-Related Side Effects and Adverse Reactions ; Genotype ; Health Occupations ; Humans ; Korea ; Leukocytes ; Mortality ; Outpatients ; Pharmacovigilance ; Prevalence ; Risk Management

BACKGROUND/AIMS: Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) are severe cutaneous adverse reactions (SCARs) that also affect the internal organs with high mortality. However, there has been no previous nationwide study of SCARs in Korea. METHODS: Cases of SCARs were recruited from the nationwide Korean Pharmacovigilance Research Network database, collected from June 2009 to December 2010, by a spontaneous reporting system. We analyzed age, gender, route of administration and the causative agents. We also reviewed previously published cases of SCARs in Korea. RESULTS: In total, 100 cases of SJS (66 cases), TEN (7 cases), and DRESS (27 cases) were reported. The mean age of the patients was 54.1 +/- 19.8 years and the proportion of males to females was 1:0.88. In total, 81 drugs were reported as causative agents: SJS (61 drugs), TEN (15 drugs), and DRESS (29 drugs). The most commonly reported causative drug was allopurinol (12 cases). Allopurinol (8 cases) and levofloxacin (2 cases) were the most commonly reported causative drugs for SJS and TEN, respectively. In DRESS, allopurinol (4 cases) and vancomycin (4 cases) were the two most common causative drugs. Anti-infective drugs were the most common drug category (75 cases). Carbamazepine was the most commonly reported causative drug according to published cases in Korea. CONCLUSIONS: Allopurinol in the spontaneous reporting system and carbamazepine in the published cases were the most common single causative drugs in SCARs in Korea. Anti-infectives were the most common drug category in the spontaneous reporting system.
Allopurinol ; Carbamazepine ; Cicatrix ; Drug Hypersensitivity ; Drug Hypersensitivity Syndrome ; Drug-Related Side Effects and Adverse Reactions* ; Eosinophilia ; Female ; Humans ; Korea ; Levofloxacin ; Male ; Mortality ; Pharmacovigilance ; Stevens-Johnson Syndrome ; Vancomycin

An 84-year-old man was admitted to our hospital with fever, jaundice, and itching. He had been diagnosed previously with chronic renal failure and diabetes, and had been taking allopurinol medication for 2 months. A physical examination revealed that he had a fever (38.8degrees C), jaundice, and a generalized maculopapular rash. Azotemia, eosinophilia, atypical lymphocytosis, elevation of liver enzymes, and hyperbilirubinemia were detected by blood analysis. Magnetic resonance cholangiography revealed multiple cysts similar to choledochal cysts in the liver along the biliary tree. Obstructive jaundice was suspected clinically, and so an endoscopic ultrasound examination was performed, which ruled out a diagnosis of obstructive jaundice. The patient was diagnosed with DRESS (Drug Rash with Eosinophilia and Systemic Symptoms) syndrome due to allopurinol. Allopurinol treatment was stopped and steroid treatment was started. The patient died from cardiac arrest on day 15 following admission.
Aged, 80 and over ; Allopurinol/adverse effects ; Biliary Tract/pathology ; Biliary Tract Diseases/diagnosis ; Bilirubin/blood ; Creatine/blood ; Drug Hypersensitivity Syndrome/*diagnosis/etiology ; Endosonography ; Eosinophils/cytology ; Humans ; Magnetic Resonance Angiography ; Male ; Tomography, X-Ray Computed